title: Low-dose radiation-induced enhancement of thymic lymphomagenesis in Lck-Bax mice is dependent on LET and gender.
abstract: The hypothesis that mitochondrial dysfunction and increased superoxide levels in thymocytes over expressing Bax (Lck-Bax1 and Lck-Bax38&1) contributes to lymphomagenesis after low-dose radiation was tested. Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice were exposed to single whole-body doses of 10 or 100 cGy of (137)Cs or iron ions (1,000 MeV/n, 150 keV/μm) or silicon ions (300 MeV/n, 67 keV/μm). A 10 cGy dose of (137)Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38&1 mice, a 100 cGy dose of high-LET iron ions caused a significant dose dependent acceleration of lymphomagenesis in both males and females that was not seen with silicon ions. To determine the contribution of mitochondrial oxidative metabolism, Lck-Bax38&1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3(-/-)/Lck-Bax38&1 mice demonstrated significant increases in thymocyte superoxide levels and acceleration of lymphomagenesis (P < 0.001). These results show that lymphomagenesis in Bax over expressing animals is enhanced by radiation exposure in both an LET and gender dependent fashion. These findings support the hypothesis that mitochondrial dysfunction leads to increased superoxide levels and accelerates lymphomagenesis in Lck-Bax transgenic mice.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Jacobus
authors.forename: Chester G
authors.initials: CG
authors.lastname: Duda
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Coleman
authors.forename: Sean M
authors.initials: SM
authors.lastname: Martin
authors.forename: Kranti
authors.initials: K
authors.lastname: Mapuskar
authors.forename: Gaowei
authors.initials: G
authors.lastname: Mao
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.forename: Peter
authors.initials: P
authors.lastname: Guida
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
mesh_terms: D000818:Animals; D002588:Cesium Radioisotopes; D004307:Dose-Response Relationship, Radiation; D005260:Female; D018628:Gene Dosage; D020450:Heavy Ions / Q000009:adverse effects*; D007501:Iron; D018499:Linear Energy Transfer; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D008223:Lymphoma / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000503:physiopathology; D010085:Oxidative Phosphorylation / Q000528:radiation effects; D018384:Oxidative Stress; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012727:Sex Characteristics; D012825:Silicon; D056566:Sirtuin 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D060168:Thymocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D013953:Thymus Neoplasms / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D014916:Whole-Body Irradiation / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C494827:Bax protein, mouse; D002588:Cesium Radioisotopes; D011993:Recombinant Fusion Proteins; C525046:Sirt3 protein, mouse; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D007501:Iron; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D056566:Sirtuin 3; D012825:Silicon